APPLICANT'S ABSTRACT: "Effect of Morphine on HumanFc Dependent and NK Cytotoxicity" investigates mechanisms of narcotic-induced immune alterations in normal human volunteers. Narcotic use in humans is associated with a variety of diseases ranging from substance abuse to the pain of cancer and surgery. Immunologic alterations in patients who suffer from these conditions may adversely affect clinical outcome. Although published studiesdocument narcotics can alter immune function in vitro and in animals, very few studies evaluate the in vivo effects of narcotics on human immunity. We studied the effect of a36-hr morphine exposure, including a 24-hour intravenous morphine infusion, on several aspects of immunity in human volunteers. This project has demonstrated the following effects of morphine in human subjects: 1) Dose-dependent suppression of peripheral blood natural killer cell cytotoxicity (NKCC). 2) Suppression of peripheral blood antibody-dependent cell cytotoxicity (ADCC). 3) Suppression of interferon gamma-induced NKCC enhancement. 4) Enhancement of lymphocyte infectivity with human immunodeficiency virus (HIV). 5) Persistence of immune alterations during effector cell incubation in morphine-free medium. 6) Increasedsensitivity of high-responder subjects to morphine-induced NKKC suppression. Significant negative results from the project include: 1) No effect from incubating effector cells in morphine-exposed serum compared to morphine-free medium. 2) No effect from a blinded 24-hour saline infusion. 3) No effect on NKCC following a briefin vivo exposure of surgical patients to high doses of narcotic. 4) No morphine effect on Fc receptor expression. The proposed project extends these observations to answer the following questions: 1) Does morphine administration alter lymphocyte subsets in peripheral blood? 2) Are morphine-induced immune alterations mediatedby the central nervous system? 3) Does morphine act through a second, suppressor cell population? 4) Does morphine alter immune function by narcotic-receptor mediated mechanisms? 5) Does serum taken from morphine-exposed subjects affect non-exposed effector cells? 6) Can morphine-induced immune suppression be prevented in vivo with interleukin-2? 7) Does invivo IL-2 exposure affect lymphocyte HlV infectivity during morphine exposure? 8) Does morphine exposure also affect HIV infectivity in monocytes? The answers to these questions have important implications for patients who use, or abuse narcotics.